Osteoporosis: the emperor has no clothes

(Another medical myth bite the dust)

Osteoporosis: the emperor has no clothes

https://onlinelibrary.wiley.com/doi/abs/10.1111/joim.12366

Abstract

Current prevention strategies for low‐trauma fractures amongst older persons depend on the notions that fractures are mainly caused by osteoporosis (pathophysiology), that patients at high risk can be identified (screening) and that the risk is amenable to bone‐targeted pharmacotherapy (treatment). However, all these three notions can be disputed.
Pathophysiology

Most fracture patients have fallen, but actually do not have osteoporosis. A high likelihood of falling, in turn, is attributable to an ageing‐related decline in physical functioning and general frailty.
Screening

Currently available fracture risk prediction strategies including bone densitometry and multifactorial prediction tools are unable to identify a large proportion of patients who will sustain a fracture, whereas many of those with a high fracture risk score will not sustain a fracture.
Treatment

The evidence for the viability of bone‐targeted pharmacotherapy in preventing hip fracture and other clinical fragility fractures is mainly limited to women aged 65–80 years with osteoporosis, whereas the proof of hip fracture‐preventing efficacy in women over 80 years of age and in men at all ages is meagre or absent. Further, the antihip fracture efficacy shown in clinical trials is absent in real‐life studies. Many drugs for the treatment of osteoporosis have also been associated with increased risks of serious adverse events. There are also considerable uncertainties related to the efficacy of drug therapy in preventing clinical vertebral fractures, whereas the efficacy for preventing other fractures (relative risk reductions of 20–25%) remains moderate, particularly in terms of the low absolute risk reduction in fractures with this treatment.

Rethinking the Appraisal and Approval of Drugs for Fracture Prevention
(complete article in link)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430022/

Lesson 1: bone density is not a reliable surrogate endpoint

By the late 1980's osteoporosis treatments could increase BMD by reducing bone resorption [calcium, calcitonin, or hormone replacement therapy (HRT)] or by stimulating bone formation (sodium fluoride). Fluoride increases BMD more than other drugs. After approval by 8 European regulators, a clinical trial challenged the reputedly positive effects of fluoride on bone fractures (Riggs et al., 1990) Compared with placebo over 4 years, sodium fluoride increased lumbar spine density by 8.2% (95%CI, 5.5–10.9) but caused a three-fold increase in non-vertebral fractures, RR = 3.2 (95%CI, 1.8–5.6). Clinical guidelines no longer recommended it. “Denser” bones may not be stronger bones.
Lesson 2: morphometric vertebral compression is not a reliable surrogate for clinical fractures

Sodium fluoride did not reduce morphometric vertebral compression (fracture), RR = 0.85 (95%CI, 0.6–1.2). Compression of a vertebra visualized by X-ray is not necessarily a clinical fracture. The deleterious effects of sodium fluoride on non-vertebral fractures could not be anticipated from data on BMD or morphometric vertebral compression.

Reductions in vertebral height between 20 and 25% at any point of the vertebrae have been defined for osteoporosis research purposes as “fractures.” However, they are not abnormalities typically considered in clinical practice as relevant to health. The inventors of this “fracture” definition acknowledged its serious limitations, warning that “fracture diagnosis could be arbitrary to some extent” (Genant et al., 1993). Some clinical trials have altered the definition. For example, in trials of risedronate and strontium ranelate “fracture” was arbitrarily redefined as a decrease in vertebral height of at least 15%. This artificially increased the reported “incidence” of “vertebral fractures.”

Only one third of all vertebral “fractures” diagnosed radiologically are symptomatic. The only osteoporosis drug trials reporting quality of life were the FIT1 and FIT2 trials of alendronate. At enrolment, 70% of women in FIT1 and 35% in FIT2 were diagnosed with vertebral “fracture,” yet 93 and 95% of women considered their self-rated health status “good, very good, or excellent” (Ware and Gandek, 1998). What was the clinical relevance of morphometric vertebral “fractures” diagnosed at baseline?
Lesson 3: clinically relevant endpoints are essential to assess harms and benefits in RCT

For treatment of osteoporosis, hip fracture is the most relevant endpoint other than total mortality. “Non-vertebral fractures” are often presented as a clinically important variable, but this raises a number of problems. Their definition varies between trials, which may facilitate “cherry-picking” of reported outcomes if the definition was not pre-specified in the trial protocol and followed scrupulously in reporting. This composite endpoint may include clinically important events (e.g., symptomatic vertebral compressions), but also inconsequential radiologically determined compressions or other minor fractures. In many trials, non-vertebral fracture outcomes are discordant with the observed incidence of hip fractures.

Bisphosphonate effects on hip fracture are disappointing. Most trials comparing alendronate, risedronate, and ibandronate with placebo showed no significant reduction of hip fractures. Meta-analysis of alendronate and risedronate compared with placebo identifies a statistically significant decrease in hip fracture incidence, but the effect size is very small and 75% of trials had a high or unclear risk of bias. The small apparent reduction in hip fracture may not be real, or is at best an exaggeration of the real benefit (Therapeutics Initiative, 2011; see Supplementary Material).
Lesson 4: assess overall harm-benefit with well-designed trials

When HRT was launched, evidence that it prevents fractures was far from compelling. Observational studies showed a decreased fracture incidence, and hypothetical cardiovascular benefits were attributed to HRT on the basis of an “improvement” in lipid profile. The first large trial (Rossouw et al., 2002) of HRT in postmenopausal women included 16,608 women aged 50–79 years, with a scheduled follow-up of some 8 years. It was stopped in 2002 after 5.2 years. Five fewer hip fractures per 10,000 person-years [HR = 0.66 (95% CI, 0.45–0.98)] and 6 fewer colorectal cancers per 10,000 person-years were observed. However, coronary heart disease, stroke, pulmonary embolism, and invasive breast cancer all increased. With a net health effect of 19 serious adverse events per 10,000 person-years, HRT's unfavorable harm-benefit ratio no longer appealed as “first-line” therapy.

Clinical trials evaluating harm-benefit balance in osteoporosis or fracture prevention should be well-powered long-term studies that include hard endpoints. Total mortality, total serious adverse events, hip fractures, and functional status are essential outcomes.
Lesson 5: drug therapy may not be more effective in high-risk patients

Aging is the main risk factor for fractures. However, there is no evidence that osteoporosis drugs perform better in elderly people. The European Public Assessment Report on zoledronic acid noted a marginal reduction in relative risk for hip fractures in patients ≥75 years (18%) compared with younger patients in Study 2301. Age subgroups pre-specified in the statistical analysis plan (<70 years; 70–74 years, and ≥75 years) included over 1,100 women each. Observed hip fracture risk increased with age in the zoledronic acid group compared with placebo, although the trend did not reach statistical significance. These results do not support the hypothesis that bisphosphonates might be more effective in high-risk populations.

A single large trial compared the effect of risedronate vs. placebo on hip fracture as the primary endpoint, depending on age (McClung et al., 2001). The mean age of women age 70–79 with osteoporosis (n = 5,445) was 74 years, vs. 83 years in women >80 with at least one risk factor for hip fracture (n = 3,886). In the older higher risk women, the placebo group had a higher total fracture risk (5.1%) than in the younger population (3.2%). However, risedronate did not reduce hip fractures in the older patient group: 4.2% with risedronate vs. 5.1% with placebo, RR = 0.8 (95% CI, 0.6–1.2).

A perfect storm for broken bones or for disease-mongering of osteoporosis?

https://www.healthnewsreview.org/2018/02/a-perfect-storm-for-broken-bones-or-for-disease-mongering/

Brody’s column promotes the idea that more drug treatment is required, when, in fact, almost everything about osteoporosis is the subject of intense debate: the link between bone density and fracture risk, the usefulness of the tests for low bone density, the role of the pharmaceutical industry in reconceptualizing risks as disease, the notorious expanding disease definitions which contribute to overdiagnosis, as well as the marketing of drugs often of minimal benefit and evidence of substantial harm.

Just stick them all on alendronic acid and ignore the side effects. Don't even think of considering vitamins D3 and K2.