Osteoporosis: treatment and teriparatide evidence

What is osteoporosis and how many people have it?

Osteoporosis is the most common metabolic bone disease in the world and stays subclinical until a fracture occurs³. Fragility fractures become increasingly common in women after age 55 and in men after 65, with substantial bone-related morbidity, higher mortality and higher health-care costs².

According to the 2017-2018 NHANES survey, age-adjusted prevalence among US adults aged 50 or older was 12.6% for osteoporosis (19.6% in women and 4.4% in men) and 43.1% for low bone mass; in women, osteoporosis rose from 14.0% to 19.6% between 2007-2008 and 2017-2018¹.

Symptoms and how osteoporosis is diagnosed

It causes no symptoms until a fracture occurs³. Any new fracture in an adult aged 50 or older signals an imminent elevated risk of further fractures, particularly in the following year, even when attributed to considerable trauma; vertebral fractures, clinical or subclinical, are the most common type³.

Diagnosis rests on bone densitometry (DXA) and fracture history. The Bone Health and Osteoporosis Foundation (BHOF) clinician's guide includes indications for densitometry and fracture-probability thresholds for treatment, and notes that the diagnosis persists even if later T-scores rise above -2.5³. Fracture-risk algorithms combining clinical risk factors and bone mineral density are now widely used to target high-risk individuals². The Endocrine Society asks that fracture risk be estimated with country-specific tools⁵. The 2020 AACE/ACE guideline clarified the diagnosis and stratifies patients into high and very high risk⁴.

Standard treatment today: what the guidelines recommend

No therapy cures the disease: antifracture drugs treat it, but skeletal deterioration resumes sooner or later when they are stopped, sooner for nonbisphosphonates and later for bisphosphonates³. Baseline measures are adequate calcium and vitamin D intake, avoiding smoking and excess alcohol, weight-bearing and resistance exercise, and fall prevention³⁵.

The American College of Physicians (ACP) living guideline (2023) recommends bisphosphonates as initial pharmacologic treatment in postmenopausal women with primary osteoporosis (strong recommendation, high-certainty evidence) and suggests them in men too (conditional, low certainty)⁶. It suggests denosumab as second line when bisphosphonates are contraindicated or poorly tolerated⁶. For women at very high fracture risk it suggests the sclerostin inhibitor romosozumab (moderate certainty) or recombinant PTH (teriparatide, low certainty), followed by a bisphosphonate⁶.

The Lancet review agrees on the scheme: at high risk the benefit-risk balance is likely favorable for up to 10 years with bisphosphonates or denosumab; at very high or imminent risk teriparatide or abaloparatide should be considered and, because their duration is restricted to 18-24 months, an antiresorptive should follow². The Endocrine Society notes that several therapies reduce fracture rates with acceptable benefit-risk profiles and that patient preferences should be incorporated⁵.

What peptide research has shown in osteoporosis

Three peptides or peptide analogues have or had a role in this disease: teriparatide (the 1-34 fragment of parathyroid hormone, PTH) and abaloparatide (an analogue of PTH-related peptide, a selective activator of the PTH type 1 receptor¹³) are anabolic; salmon calcitonin is antiresorptive. The wider history of peptides as drugs is in A century of peptide therapeutics.

Teriparatide (PTH 1-34). It is FDA-approved: the Forteo label indicates treatment of postmenopausal women with osteoporosis at high fracture risk, or who have failed or are intolerant to other therapy, and states that it reduces the risk of vertebral and nonvertebral fractures; it also indicates it to increase bone mass in men with primary or hypogonadal osteoporosis and for glucocorticoid-induced osteoporosis⁷. In the pivotal randomized trial of 1637 postmenopausal women with prior vertebral fractures, new vertebral fractures occurred in 14% on placebo and in 5% and 4% on the two PTH doses (relative risks 0.35 and 0.31); nonvertebral fragility fractures occurred in 6% versus 3% (relative risks 0.47 and 0.46), after a median of 21 months⁸. In 437 men, lumbar density rose 5.9% and 9.0% above baseline depending on dose, although the study was stopped after a median of 11 months because of osteosarcoma findings in rats⁹.

The VERO trial compared teriparatide with risedronate using fractures as the primary outcome, unusual among osteoporosis drugs: in 680 women per group with severe osteoporosis, new vertebral fractures at 24 months were 5.4% with teriparatide and 12.0% with risedronate (risk ratio 0.44; 95% CI 0.29-0.68), and clinical fractures 4.8% versus 9.8% (hazard ratio 0.48)¹⁰. Nonvertebral fragility fractures were 4.0% versus 6.1% (hazard ratio 0.66; 95% CI 0.39-1.10), a nonsignificant difference¹⁰. The manufacturer funded the trial¹⁰.

Abaloparatide. It is also FDA-approved: the Tymlos label indicates treatment of postmenopausal women with osteoporosis at high fracture risk (it reduces vertebral and nonvertebral fractures) and to increase bone density in men with osteoporosis at high risk¹². In its phase 3 study (ACTIVE, 2463 women), new vertebral fractures at 18 months were 0.6% with abaloparatide versus 4.2% with placebo (relative reduction 86%, absolute 3.6%) and nonvertebral fractures 2.7% versus 4.7% (p = 0.049) according to the label¹²¹³. After 18 months of abaloparatide or placebo followed by 24 months of alendronate (ACTIVExtend), 0.9% versus 5.6% had a new vertebral fracture over 43 months; the authors include manufacturer employees, and the analysis for regulators found no hip fractures in the abaloparatide/alendronate group versus five in placebo/alendronate¹⁴. Teriparatide, in ACTIVE's open-label comparison arm, had more hypercalcemia than abaloparatide (6.4% versus 3.4%)¹³.

Salmon calcitonin. It is an antiresorptive peptide whose role is now limited. In the PROOF study (1255 women, 5 years), only the middle dose of the nasal spray reduced new vertebral fractures (relative risk 0.67; 95% CI 0.47-0.97); the lower and higher doses did not differ from placebo¹⁶. A meta-analysis found that calcitonin probably reduces vertebral fractures, but the effect in small trials (relative risk 0.46) was larger than in the single large trial (0.79) and the effect on nonvertebral fractures remained uncertain¹⁷. Today the injection label indicates it for postmenopausal osteoporosis only when alternatives are not suitable and states that fracture-reduction efficacy has not been demonstrated¹⁵.

An important nuance: the other bone-forming drug the guidelines cite, romosozumab (compared with alendronate in the ARCH trial), is an antibody, not a peptide⁶²⁰. In osteoporosis the peptide spotlight belongs to the PTH analogues. How other peptides relate to bone is covered in GLP-1s: interactions, bone, micronutrients and in Endometriosis: what it is, treatment and the GnRH evidence, where bone loss limits treatment duration.

Safety: adverse effects and precautions

Teriparatide. The label says to avoid use in patients at increased risk of osteosarcoma (open epiphyses, metabolic bone disease other than osteoporosis including Paget's disease, bone metastases or a history of skeletal malignancy, prior skeletal radiation, or hereditary predisposing disorders) and in those with an underlying hypercalcemic disorder; it warns of transient orthostatic hypotension with initial doses, urolithiasis, hypersensitivity and the risk of digoxin toxicity⁷. Use for more than 2 years during a patient's lifetime should be considered only if the patient remains at or has returned to high fracture risk⁷. The osteosarcoma concern arose from rat studies⁹; a 15-year US surveillance study identified 3 osteosarcoma cases with prior teriparatide use versus 4.17 expected (standardized incidence ratio 0.72; 90% CI 0.20-1.86) and concluded that incidence did not differ from the background rate¹¹. It is observational, with interviews completed for 24% of cases¹¹.

Abaloparatide. Its label says it is unknown whether it causes osteosarcoma in humans and that no increased risk has been observed in observational studies; it warns of orthostatic hypotension, typically within 4 hours of injection, hypercalciuria and urolithiasis, and does not recommend it with pre-existing hypercalcemia or for more than 2 years in a lifetime¹². In women, common reactions versus placebo were hypercalciuria 11% versus 9%, dizziness 10% versus 6%, nausea 8% versus 3%, headache 8% versus 6% and palpitations 5% versus 0.4%¹².

Calcitonin. The label warns of hypocalcemia with tetany and seizures (to be corrected before starting), serious hypersensitivity reactions and, in the analysis of randomized trials, malignancy incidence of 4.1% with calcitonin versus 2.9% with placebo, suggesting an increased risk that cannot be excluded¹⁵. A review with meta-analysis concluded that the association is weak and causality unlikely¹⁹, while another noted that in 15 of 18 studies the malignancy percentage was higher with calcitonin, using poor-quality cancer assessment methods¹⁸.

Summary by agent

Frequently asked questions

Are there approved peptides for osteoporosis? Yes: teriparatide and abaloparatide hold FDA indications for postmenopausal women with osteoporosis at high fracture risk, and salmon calcitonin holds one when alternatives are not suitable⁷¹²¹⁵.

Are they the first treatment for osteoporosis? No. The ACP guideline recommends bisphosphonates to start; PTH analogues are suggested only at very high fracture risk, followed by a bisphosphonate⁶.

How long can they be used? The abaloparatide label does not recommend more than 2 years in a lifetime, and the teriparatide label limits use beyond 2 years to patients who remain at high risk⁷¹². An antiresorptive follows².

Does teriparatide cause bone cancer? It caused osteosarcoma in rats, but a 15-year US surveillance study found no incidence higher than expected (standardized incidence ratio 0.72)⁹¹¹. The label still asks to avoid it in patients at increased osteosarcoma risk⁷.

Is teriparatide better than an oral bisphosphonate? In VERO, in women with severe osteoporosis, there were fewer vertebral and clinical fractures with teriparatide than with risedronate at 24 months, with no significant difference in nonvertebral fractures¹⁰.

Is calcitonin still used? Its use has declined: the label reserves it for when alternatives are not suitable, states that fracture reduction has not been demonstrated and warns of a possible increase in malignancies¹⁵.